Derivatives of 1, 2, 4-benzothiadiazine-1, 1-dioxides



United States Patent 3,344,140 DERIVATIVES OF 1,2,4-BENZOTIHADIAZHNE- LI-DIQXIDES Bernard Loev, Broomall, Pa, assignor to Smith Kline & French Laboratories, Philadelphia, Pin, a corporation of Pennsylvania No Drawing. Original application Feb. 27, 1963, Ser. No. 261,481. Divided and this application June 21, 1966, Ser. No. 559,123

8 Claims. (Cl. 26ti243) This application is a division of Serial No. 261,481 filed February 27, 1963 now abandoned.

This invention relates to novel 7-carbamoylsulfamoyl- 2H 1,2,4 benzothiadiazine-l,l-dioxodies having pharmacodynamic activity, in particular having diuretic and hypotensive activity. In addition, this invention relates to novel carbamoylsulfamoylanline intermediates.

The new 7-carbamoylsulfamoyl-ZH-1,2,4-benzothiadiazine-l,l-dioxides of this invention are represented by the following formulas.

Formula I 1F: I H R R R H) \NCHNSOP s R5 02 and Formula II N R; \R3 a f. l

N-R NCHNSO2 \s/ R5 02 when:

R is hydrogen, halogen, trifiuoromethyl, lower alkyl,

lower alkoxy or amino;

R is hydrogen or lower alkyl:

R, is hydrogen, lower alkyl, halo lower alkyl, phenyl, phenylalkyl such as benzyl or phenethyl, cycloalkyl, cycloalkyl-alkyl such as cyclopentylmethyl or cyclohexylmethyl, cycloalkenylalkyl such as cyclopentenylmethyl or cyclohexenylmethyl, phenoxyalkyl such as phenoxymethyl or phenylthioalkyl such as phenylthiomethyl;

R is hydrogen or R is lower alkyl, cycloalkyl such as cyclopentyl or cyclohexyl or phenylalkyl such as benzyl or phenethyl; and

R is hydrogen or, when R is lower alkyl, lower alkyl or, when taken together with R and the nitrogen atom to which they are attached, N-pyrrolidinyl or N-piperidyl.

Advantageous compounds of this invention are represented by Formulas I and II when: R is halogen or trifiuoromethyl, R is hydrogen;

Patented Sept. 26, 1967 R is hydrogen, lower alkyl, halo lower alkyl or benzyl; R is hydrogen or R is lower alkyl, cyclopentyl or cyclohexyl; and R is hydrogen.

Novel carbamoylsulfamoylaniline compounds useful as intermediates in the preparation of benzothiadiazine derivatives of Formulas I and II are further objects of this invention and are represented by the following formula.

Formula III in which:

The terms lower alkyl and lower alkoxy where used herein denote groups having 1 to 6 carbon atoms. The term cycloalkyl denotes groups having 3 to 6 carbon atoms.

Benzothiadiazine derivatives of this invention are prepared by the following procedures.

trifiuoromethyl, lower alkyl,

Procedure A The terms R R R R and R are as defined above.

According to Procedure A, a 7-sulfamoyl-2H-1,2,4-benzothiadiazide-l,l-dioxide is reacted with the appropriate isocyanate. The reaction is carried out in aqueous solution or in an inert solution such as acetone or a lower alkanol, for example ethanol, in the presence of a base such as alkali metal hydroxide or carbonate or a tertiary amine, for example triethylamine, at about O45 C. Working up by removing the solvent acidifying the solution and filtering gives a mixture of 7-carbamoylsu1famoyl and 2-carbamoyl-7-carbamoylsulfamoyl benzothiadiazines which are separated, for example, by chromatography.

3 Procedure B B1 -NHR2 RSNCO R NHR2 l HgNS Oz SO2NHa RHNCHNSO: S OzNHR 5 RBOHO/ H N R1 \/R3 I NH R5HNCHNSO2 \s/ 2 N R1 i-Ra mrmirmvsm- 39* s The terms R R R R and R are as defined above. According to Procedure B, a 2,4-disulfamoylaniline is reacted with an excess of the appropriate isocyanate to give, after separating the resulting isomers, for example, by chromatography, the 2 sulfamoyl-4-carbamoylsulfamoylaniline and the 2,4-di-(carbamoylsulfamoyl)aniline intermediates. The 2-sulfamoyl-4-carbamoylsulfamoylaniline intermediate is reacted with an appropriate aldehyde to give the products of Formula I. Reacting the 2-sulfamoyl-4-carbamoylsulfamoylaniline or the 2,4-di- 3n (earbamoylsulfamoyl)aniline intermediate with an ortho ester such as ethyl orthoformate, a carboxylic acid or an acid anhydride gives the products of Formula II.

Pr 0 d C 0 e are a s H N NCOCl R. 1 s.

6 N-H HSNSO S/ T z N \4 s 6 l NCHNSO S Rs 02 R1 N Ra NCOCl l N-H H N80 R R BK g 1 l 3 NCHNSO: s R6 02 The terms R R R R R and R are as defined above.

According to Procedure C, a 3,4-dihydro-7-sulfamoyl- 2H-1,2,4-benzothiadiazide-1,l-dioxide is reacted with one mole of an N-substituted carbamoylchloride to give the 7-carbamoylsulfamoyl compounds of Formula I or a 7-sulfamoyl-2H-1,2,4-benzothiadiazine-l,l-dioxide is re- 69 acted with one or two moles of an N-substituted carbamoylchloride to give the compounds of Formula II. The reaction is carried out in an inert solvent such as acetone or a lower alkanol, for example ethanol or iso- F propanol, in the presence of a base such as an alkali metal carbonate or hydroxide, for example sodium carbonate or sodium hydroxide.

Alternatively, the dihydro products or Formula I are prepared by catalytic hydrogenation of corresponding products of Formula II.

The following examples are not limiting but are illustrative of the compounds of this invention and the processes for their preparation.

EXAMPLE 1 A solution of 3.32 g. n-butylisocyanate in acetone is added to a stirred solution of 10 g. of 6-chloro-3,4-dihydro-7-sulfamoyl 2H 1,2,4 benzothiadiazine 1,1-dioxide in 35 ml. of 1 N sodium hydroxide and 34 ml. acetone at 510 C. The solution is stirred an additional two hours at 5 C., then two hours at room temperature. The acetone is removed in vacuo at 40 C. and the solution is then acidified. The resulting White solid is filtered, then dissolved in methanol and treated with ether to give 7-(n-butylcarbamoyl)sulfamoyl-6-chloro-3,4-dihydro-ZH-1,2,4-benzothiadiazine-1,1-dioxide.

EXAMPLE 2 To a stirred mixture of 9.9 g. of 6-chloro-7-sulfamoyl- 2H-1,2,4-benzothiadiazine-1,1-dioxide in 35 ml. of l N sodium hydroxide and 35 ml. of acetone at 5 C. is added 3.4 g. of n-butylisocyanate in acetone. The resulting mixture is stirred for two hours at room temperature to give, after working up as in Example 1, 7-(n-butylcarbamoyl) sulfamoyl-6-chloro 2H 1,2,4 -benzothiadiazine-l,1-dioxide,

EXAMPLE 3 By the procedure of Example 1, using in place of n-butylisocyanate, 0.03 m. of:

methylisocyanate, cyclohexylisocyanate, benzylisocyanate and phenethylisocyanate there is obtained:

6 chloro 3,4 dihydro 7 (methylcarbamoyl)sulfarnoyl 2H 1,2,4 benzothiadiazine 1,1 dioxide and the corresponding 7-(cyclohexylcarbamoyl), 7- (benzylcarbamoyl) and 7-(phenethylcarbamoyl) derivatives, respectively.

EXAMPLE 4 A solution of 7.8 g. of n-butylisocyanate is added to 10.0 g. of 5-chlor0-2,4-disulfamoylaniline in 79 ml. of 1 N sodium hydroxide and 80 ml. of acetone at 10 C. The resulting solution is stirred at 10 C. for two hours, then at room temperature for two hours. The acetone is removed in vacuo and the residue is acidified with dilute hydrochloric acid. The solid material is recrystallized from aqueous ethanol to give 5-chloro-2,4-bis-(n-butylcarbamoyl)sulfamoylaniline. From the filtrate S-chloro- 4-(nbutylcarbamoyl)sulfamoyl-2-sulfamoylaniline is isolated by concentrating, filtering and fractionally crystallizing.

A mixture of 8.0 g. of 5-chloro-2,4-bis-(n-butylcarbamoyl)sulfamoylaniline and 25 ml. of ethyl orthoformate is heated at -120 C. for one hour. After evaporating the excess ethyl orthoformate in vacuo, dissolving the residue in methanol and adding ether, the product is 2 n-butylcarbamoyl-7-(n butylcarbamoyl)sulfamoyl- 6-chloro-2H-1,2,4-benzothiadiazine-1,1-dioxide.

EXAMPLE 5 According to the procedure of Example 4 using in place of 5-chloro-2,4-disulfamoylaniline:

5-bromo-2,4-disulfamoylaniline 2,4-disu1famoylaniline 5-methyl-2,4-disulfamoylaniline and 5-methoxy-2,4-disulfamoylaniline the products obtained are: 6-bromo-2-n-butylcarb amoyl-7- (n-butylcarbamoyl) sulfamoyl-ZH-l,2,4-benzothiadiazine-1, l-dioxide 2-n-butylcarbamoyl-7-(n-butylcarbamoyl)sulfamoyl-ZH- 1,2,4-benzothiadiazine-1,1-dioxide 2-n-butylcarbamoyl-7-(n-butylcarbamoyl)sulfamoyl-6- methyl-2H-1,2,4-benzothiadiazine-1,1-dioxide and 2-n-butylcarbamoyl-7- (n-butylcarb amoyl) sulfamoyl-6- methoxy 2H-1,2,4-benzothiadiazine-1,l-dioxide, respectively.

EXAMPLE 6 An acetone solution of 5.0 g. of n-butylisocyanate is added with stirring to 16.4 g. of 7-sulfamoyl-6-trifluoromethyl-2H-l,2,4-benzothiadiazine-1,1-dioxide in 55 ml. of l N sodium hydroxide and 55 ml. of acetone at l0 C. The stirring is continued for two hours at 5 C., then at room temperature for two hours. Working up as in Example 1 gives 7-(n-butylcarbamoyl)sulfamoyl-6-trifluoromethyl-2H-1,2,4-benzothiadiazine-l,l-dioxide.

Similarly, using 3,4-dihydro-7-sulfamoyl-6-trifluoromethyl-ZH-1,2,4-benzothiadiazine-1,1-dioxide as the Starting material, the product is 7-(n-butylcar-bamoyl)sulfamoyl 3,4 dihydro 6 trifiuoromethyl 2H 1,2,4- benzothiadiazine-1,1-dioxide.

EXAMPLE 7 An acetone solution of 14.4 g. of 5-chloro-N-methyl- 2,4-disulfamoylaniline, 4.5 g. of n-propylisocyanate and 100 ml. of 1 N sodium hydroxide is stirred at 5-10" C. for two hours, then at room temperature for three hours. Working up as in Example 4 and separating the resulting isomers by chromatography gives S-chloro-N-methyl-Z- sulfamoyl-4-n-propylsulfamoylaniline. Heating this intermediate With 50 ml. of aqueous formaldehyde, 300 ml. of methanol and ml. of aqueous sodium hydroxide for two hours at reflux and working up by acidifying with concentrated hydrochloric acid, concentrating and recrystallizing the residue gives 6-chloro-3,4-dihydro-4- methyl 7 n propylsulfamoyl 2H 1,2,4 benzothiadiazine-1,1-dioxide.

Using acetaldehyde in the above reaction, the product is 6 chloro 3,4 dihydro 3,4 dimethyl 7 n propylsulfamoyl-ZH-1,2,4-benzothiadiazine-1,l-dioxide.

EXAMPLE 8 A mixture of 5.0 g. of 5-chloro-4-(n-butylcarbamoyl) sulfamoyl-2-sulfamoylaniline (prepared as in Example 4) and 5.8 g. of dichloroacetal in ethanolic hydrogen chloride is heated at reflux for five hours. Concentrating, adding chloroform, cooling and filtering gives 7-(n-butylcarbamoyl)sulfamoyl 6 chloro 3 dichloromethyl- 3,4-dihydro-2I- -l,2,4-benzothiadiazine-1,1-dioxide.

By a similar procedure using, in place of dichloroacetal, the following:

phenylacetaldehyde fiphenyl propionaldehyde propionaldehyde and butyraldehyde there is obtained:

3-benzyl-7- (n-butylcarbamoyl) sulfamoyl-6-chloro-3,4-

dihydro-2H-1,2,4-benzothiadiazine-l, l-dioxide 7- (n-butylcarb amoyl sulfamoyl-6-chloro-3,4-dihydro-3- phenethyl-ZH-l,2,4-benzothiadiazine-1,1-dioxide 7- (n-butylcarbamoyl) sulfamoyl-6-chloro-3-ethyl-3,4-

dihydro-2H-1,2,4-benzothiadiazine-1,l-dioxide and 7- (n-butylcarbamoyl) sulfamoyl-6-chloro-3,4-dihydro-3- propyl-2H-1,2,4-benzothiadiazine-1, l-dioxide,

respectively.

EXAMPLE 9 A mixture of 9.9 g. of 6-chloro-3,4-dihydro-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,l-dioxide, 3.6 g. of dimethylcar-bamoyl chloride and 1.5 g. of sodium hydroxide in acetone is stirred at room temperature for three hours. Concentrating in vacuo, acidifying and filtering givess 6 chloro 3,4 dihydro 7 dimethylcarbamoylsulfam- 0yl-2H-1,2,4-benzothiadiazine-l,l-dioxide.

By the same procedure, reacting equivalent amounts of 6 trifiuoromethyl 7 sulfamoyl 2H 1,2,4 benzothiadiazine-1,1-dioxide and diethylcarbamoyl chloride, the product is 7-diethylcarbamoylsulfamoyl-6-trifluoromethyl-ZH-l ,2,4-benzothiadiazine-1, l-dioxide.

6 EXAMPLE 10 By the procedure of Example 9, 6-chloro-3,4-dihydro- 7 sulfamoyl 2H 1,2,4 benzothiadiazine 1,1 dioxide is reacted with an equimolar amount of l-piperidinecarbonyl chloride in the presence of sodium hydroxide in ethanol to give 6-chloro-3,4-dihydro-7-(l-piperidylcarbonyl)sulfamoyl 2H 1,2,4 benzothiadiazine 1,1- dioxide.

Similarly, using l-pyrrolidinecar-bonyl chloride in place of l-piperidinecarbonyl chloride, the product is 6-chloro- 3,4 dihydro 7 (1 pyrrolidinecarbonyl)sulfamoyl- 2H-1,2,4-benzothiadiaZine-l,l-dioxide.

EXAMPLE 11 To a mixture of 16.8 g. of 6-chloro-3-cyclopropyl-7- sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxide and 60 m1. of 1 N sodium hydroxide in acetone at 5 C. is added 5.0 g. of n-propylisocyanate in acetone. The resulting mixture is stirred for two hours at 5 (3., then two hours at room temperature. Working up as in Example 1 gives 6 chloro 3 cyclopropyl 7 (n propylcarbamoyl) sulfamoyl 2H 1,2,4-benzothiadiazine-1,l-dioxide. From the filtrate there is obtained, by concentrating, filtering and recrystallizing, 6-chloro-3-cyclopropyl-2-(n-propyl) carbamoyl 7 (n propylcarbamoyl)sulfamoyl 2H- 1,2,4-benzothiadiazine-1,1-dioxide.

Similarly, using as the starting material 6-chloro-3- cyclopentyl 7 sulfamoyl 2H 1,2,4 benzothiadiazine- 1,l-dioxide, the products are 6-chloro-3-cyclopentyl-7-(npropylcarbamoyl)sulfamoyl 2H 1,2,4 benzothiadiazine-1,1-dioxide and the corresponding 2-(n-propyl)carbamoyl derivative.

Using 3-(2-cyclopentenyl) methyl-3,4-dihydro 7 sulfamoyl-6-trifluoromethyl-2H-1,2,4 benzothiadiazine-1,1- dioxide as the starting material in the above procedure and working up as in Example 1 gives 3 (2-cyclopentenyl)- methyl-3,4-dihydro 7 (n-propylcarbam-oyl)sulfamoyl- 2H-1,2,4- benzothiadiazine-1,1-dioxide.

Using 6-chloro-3-cyclopentylmethyl 3,4 dihydro-7- sulfam0yl-2H-1,2,4-benzothiadiazine-1,1 dioxide as the starting material in the above procedure and working up as in Example 1, 6-chloro-3-cyclopentylmethy1 3,4 dihydro-7-(n-propylcarbamoyl)sulfamoyl 2H 1,2,4 benzothiadiazine-1,1-dioxide is obtained.

EXAMPLE 12 Ten grams of 6-chloro-3,4-dihydro-3-phenoxymethyl- 7-sulfamoyl-2H1,2,4-benzothiadiazine 1,1 dioxide and 2.5 g. of n-butylisocyanate are stirred for two hours at 510 C. in acetone solution containing 1 N sodium hydroxide. After additional stirring for two hours at room temperature and working up as in Example 1, 7-(n-butylcarbamoyl)sulfamoyl-6-chloro-3,4-dihydro 3 phenoxymethyl-ZH-1,2,4-benzothiadiazine-1,l-dioxide is obtained.

Similarly, using 6-chloro-3,4-dihydro-3-phenylmercaptomethyl-7-sulfamoyl-2H-1,2,4-benzothiadiazine 1,1 dioxide as the starting material, 7-(n-butylcarbamoyl)sulfamoyl-6-chloro-3,4-dihydro 3 phenylthiomethyl 2H- 1,2,4-benzothiadiazine-l,l-dioxide is obtained.

What is claimed is:

1. A compound selected from the group consisting of compounds having the following formulas:

Formula I H N 4- MR3 K n NOHNS 02 N41 s R6 03 7 Formula II N R1 R3 e R I Nounsor s Ru in which:

R is a member selected from the group consisting of hydrogen, halogen, trifiuorornethyl, lower alkyl, lower alkoxy and amino;

R is a member selected from the group consisting of hydrogen and lower alkyl;

R is a member selected from the group consisting of hydrogen, lower alkyl, halo lower alkyl, phenyl, benzl, phenethyl, cycloalkyl, cyclopentylmethyl, cyclohexylmethyl, cyclopentenylmethyl, cyclohexenylmethyl, phenoxymethyl and phenylthiornethyl;

R is a member selected from the group consisting of hydrogen and R is a member selected from the group consisting of lower alkyl, cyclopentyl, cyclohexyl, benzyl and phenethyl; and

R is a member selected from the group consisting of hydrogen and, when R is lower alkyl, lower alkyl and, when taken together with R and the nitrogen atom to which they are attached, N-pyrrolidinyl and N-piperidyl.

2. A compound according to Formula I of claim 1 in which R is chloro, R and R are hydrogen, R is lower alkyl and R is hydrogen, said compound being 6-chloro- 3,4-dihydro-7 (lower alkylcarbamoyDsulfamoyl 2H- 1,2,4-benzothiadiazine-1,l-dioxide.

3. A compound according to Formula I of claim 1 in which R is chloro, R and R are hydrogen, R is n-butyl and R is hydrogen, said compound being 7-(n-butylcarbamoyl)sulfarnoyl-6-chloro-3,4-dihydro-2I-I 1,2,4 benzothiadiazine-l,l-dioxide.

4. A compound according to Formula I of claim 1 in which R is trifluoromethyl, R and R are hydrogen, R is lower alkyl and R is hydrogen, said compound being 3,4-dihydro-7-(lower alkylcarbamoyhsulfamoyl 6 trifiuoromethyl-ZH-l,2,4-benzothiadiazine-1,l-dioxide.

5. A compound according to Formula I of claim 1 in which R is chloro, R is hydrogen, R is dichloromethyl, R is lower alkyl and R is hydrogen, said compound being 6-chloro-3-dichloromethyl-3,4-dihydro 7 (lower alkylcarbamoyl)sulfamoyl-2H-1,2,4 benzothiadiazine 1,1- dioxide.

6. A compound according to Formula I of claim 1 in which R is chloro, R is hydrogen, R is benzyl, R is lower alkyl and R is hydrogen, said compound being 3- benzyl-6-chloro-3,4-dihydro-7 (lower alkylcarbamoyl)- sulfamoyl-ZH-1,2,4-benzothiadiazine-l,l-dioxide.

7. A compound according to Formula I of claim 1 in which R is chloro, R is hydrogen, R is ethyl, R is lower alkyl and R is hydrogen, said compound being 6-chloro- 3-ethyl-3,4-dihydro-7 (lower alkylcarbamoyl)sulfamoyl- 2H-1,2,4-benzothiadiazine-l,l-dioxide.

8. A compound according to Formula II of claim 1 in which R is chloro, R R and R are hydrogen, R is n-butyl and R is hydrogen, said compound being '7-(nhutylcarbarnoyl)sulfamoyl-6-chloro-2H-1,2,4 benzothiadiazine-l,l-dioxide.

References Cited UNITED STATES PATENTS 3,252,975 5/1966 De Stevens et al. 260 --243 NICHOLAS S. RIZZO, Primary Examiner;

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,344,140 September 26, 1967 Bernard Loev It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, lines 32 to 37 and column 7, lines 2 to 6, the formula, each occurrence, should appear as shown below instead of as in the patent:

column 2, lines 48 to 52, the formulas should appear as shown below instead of as in the patent:

N N 1 I T RSNCO i R1 R HN HNSO HZNSOZ S H 5 2 S/N--R4 Signed and sealed this 29th day of October 1968.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THE FOLLOWING FORMULAS: 